Impaired Integrated Stress Response and Mitochondrial Integrity Modulate Genotoxic Stress Impact and Lower the Threshold for Immune Signalling

Autor:	Mihaela Temelie, Rubab Talpur, Marta Dominguez-Prieto, Ayanda Dantas Silva, Constantin Cenusa, Liviu Craciun, Diana Iulia Savu, Nicoleta Moisoi
Rok vydání:	2023
Předmět:	Inorganic Chemistry Organic Chemistry General Medicine Physical and Theoretical Chemistry DNA damage mitochondria function integrated stress response radioinduced signalling pathways Molecular Biology Spectroscopy Catalysis Computer Science Applications
Zdroj:	International Journal of Molecular Sciences; Volume 24; Issue 6; Pages: 5891
ISSN:	1422-0067
DOI:	10.3390/ijms24065891
Popis:	open access article Mitochondria–nucleus communication during stress dictates cellular fate with consequences on the etiopathology of multiple age-related diseases. Impaired mitochondrial quality control through loss of function of the mitochondrial protease HtrA2 associates with accumulation of damaged mitochondria and triggers the integrated stress response, implicating the transcription factor CHOP. Here we have employed a combined model of impaired mitochondria quality control, namely HtrA2 loss of function, and/or integrated stress response, namely CHOP loss of function, and genotoxicity to address the distinctive roles of these cellular components in modulating intracellular and intercellular responses. The genotoxic agents employed were cancer therapeutic agents such as irradiation with X-ray and protons or treatment with the radiomimetic bleomycin. The irradiation had an enhanced effect in inducing DNA damage in cells with CHOP loss of function, while the bleomycin treatment induced more DNA damage in all the transgenic cells as compared to the control. The genetic modifications impaired the transmission of DNA damage signalling intercellularly. Furthermore, we have dissected the signalling pathways modulated by irradiation in selected genotypes with RNA sequencing analysis. We identified that loss of HtrA2 and CHOP function, respectively, lowers the threshold where irradiation may induce the activation of innate immune responses via cGAS-STING; this may have a significant impact on decisions for combined therapeutic approaches for various diseases.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3ddf6c4d31d08aa47c7aa74d319880e1 https://doi.org/10.3390/ijms24065891 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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